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Wnt Signaling Networks in Autism Spectrum Disorder and Intellectual Disability Vickie Kwan, Brianna K

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Wnt Signaling Networks in Autism Spectrum Disorder and Intellectual Disability Vickie Kwan, Brianna K Kwan et al. Journal of Neurodevelopmental Disorders (2016) 8:45 DOI 10.1186/s11689-016-9176-3 REVIEW Open Access Wnt signaling networks in autism spectrum disorder and intellectual disability Vickie Kwan, Brianna K. Unda and Karun K. Singh* Abstract Background: Genetic factors play a major role in the risk for neurodevelopmental disorders such as autism spectrum disorders (ASDs) and intellectual disability (ID). The underlying genetic factors have become better understood in recent years due to advancements in next generation sequencing. These studies have uncovered a vast number of genes that are impacted by different types of mutations (e.g., de novo, missense, truncation, copy number variations). Abstract: Given the large volume of genetic data, analyzing each gene on its own is not a feasible approach and will take years to complete, let alone attempt to use the information to develop novel therapeutics. To make sense of independent genomic data, one approach is to determine whether multiple risk genes function in common signaling pathways that identify signaling “hubs” where risk genes converge. This approach has led to multiple pathways being implicated, such as synaptic signaling, chromatin remodeling, alternative splicing, and protein translation, among many others. In this review, we analyze recent and historical evidence indicating that multiple risk genes, including genes denoted as high-confidence and likely causal, are part of the Wingless (Wnt signaling) pathway. In the brain, Wnt signaling is an evolutionarily conserved pathway that plays an instrumental role in developing neural circuits and adult brain function. Conclusions: We will also review evidence that pharmacological therapies and genetic mouse models further identify abnormal Wnt signaling, particularly at the synapse, as being disrupted in ASDs and contributing to disease pathology. Keywords: Autism spectrum disorders, ASD, Synapse, Wnt signaling, GSK3, Neurodevelopment, Signaling, Plasticity, Mutations, Neurotransmission, Neurogenesis, Neuronal migration Background networks important for proper brain development. The emerging genetic landscape of Wnt signaling in ASDs While the spectrum of ASDs is reflected by the multiple ASDs and other psychiatric disorders may have heritabil- individual risk genes and loci, there is some common de- ity estimates greater than 90% [1], suggesting a strong nominator between affected individuals, which strongly genetic component to disease. With this background in suggests that disruption of the core neurodevelopmental mind, there has been an enormous advancement of new signaling pathways leads to disease symptoms. In this re- genetic technologies to discover risk-causing genes and view, we will examine accumulating evidence for the in- loci. These developments paired with an increased ability volvement of Wnt signaling in developmental cognitive to process large data sets have led to many new risk disorders. This includes emerging genetic data from genes being discovered. The number of genes and large sequencing studies, clinically used medications, chromosomal loci linked to ASDs is growing, making it and mouse models. We will also present potential ave- difficult to determine which one(s) to study. This has in- nues for therapeutic approaches, and how Wnt signaling spired the field to determine if there are links between may be modulated for treatment of patient symptoms by the genes and whether they converge into signaling leveraging clinical trial data from other fields. * Correspondence: [email protected] Department of Biochemistry and Biomedical Sciences, Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario L8S 4K1, Canada © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kwan et al. Journal of Neurodevelopmental Disorders (2016) 8:45 Page 2 of 10 Making sense of genetic findings nucleus and can act as a transcription factor that modu- It is no surprise that the clinical heterogeneity of ASDs lates the expression of target genes (Fig. 1); and (ii) can be explained, at least in part, by the large number of “non-canonical” β-catenin-independent signaling [17]. genetic mutations found through next-generation se- Interestingly, many of the proteins in both signaling quencing. The number of mutations discovered ranges pathways localize to the synapse and play important in the several hundreds, according to well-known functions in synaptic growth and maturation [18–23]. sources such as the Simons Foundation Autism Research There are now multiple lines of evidence implicating this Initiative (SFARI). There is much difficulty in trying to pathway in the etiology and pathophysiology of ASD and understand the biological etiology of ASDs when so intellectual disability (ID). While the human genetic data many genes are involved. One hypothesis is that the gen- is an important supporting factor, it is not the only one. etic lesions disrupt specific signaling pathways during There are a number of mouse genetic knockout (KO) discrete time points of brain development. For example, models targeting Wnt signaling molecules, describing many of the initial genetic studies identified genes in- molecular, cellular, electrophysiological, and behavioral volved in synapse development and refinement. This was deficits that are consistent with ASD and ID. Further- largely based on findings that multiple genes in syn- more, the genes involved in Wnt signaling are of signifi- dromic forms of ASDs (e.g., Fragile X syndrome (FMR1), cant clinical interest because there are a variety of Rett syndrome (MECP2), Angelman syndrome (UBE3A), approved drugs that either inhibit or stimulate this and genes that cause non-syndromic forms of ASDs pathway. (e.g., the Shank and neuroligin/neurexin family of pro- teins) have important roles during synapse development Genetic evidence implicating Wnt signaling genes and and refinement [2–8]. This suggests that the disruption support by cellular models of postnatal synaptic maturation could increase the risk CHD8 for developing ASDs and related disorders. However, The strongest single candidate gene for non-syndromic there has been accumulating evidence that other brain ASDs is chromodomain helicase DNA binding protein 8 developmental milestones are also vulnerable, such as (CHD8) [24–30]. There are multiple de novo, truncating, prenatal brain development (e.g., neurogenesis) [9], or or missense mutations discovered in CHD8 in individ- postnatal development of non-neuronal cells (e.g., oligo- uals with ASDs [27–29, 31–34]. CHD8 is found at active dendrocytes during myelination and microglia function) transcription sites with histone modifications H3K4me3 [10–13]. This is also supported by the implication of or H3K27ac, and it is thought to directly activate genes discrete cell types in the brain based on the identifica- by binding near the transcriptional start site and pro- tion of specific risk genes expressed in those cells (e.g., moting transcription factor activity or recruitment. It inhibitory neurons) [14–16]. In the current review, we can also indirectly impact transcription by interacting take an alternative approach that is not in contrast to with modified histone sites and other co-regulators to these hypotheses but examines whether there is conver- make chromatin more assessable [24, 34–36]. Interest- gence of multiple risk genes onto specific signaling path- ingly, one of the major pathways regulated by CHD8 is ways, which ultimately impact multiple cell types and/or canonical Wnt signaling [37, 38]. Previous work charac- developmental processes. We put forth the notion that terized CHD8 as a negative regulator of canonical Wnt by focusing on a specific pathway and dissecting which signaling, which fits with the hypothesis that elevated ca- molecular players in that pathway are important for dis- nonical Wnt signaling activity causes excessive prolifera- ease pathophysiology, it may offer an opportunity to tion of embryonic neural progenitor cells (NPCs) in the identify key proteins to be pharmacologically targeted by brain and may in part explain the macrocephaly (“big drug therapies to treat these disorders. brain”) phenotype observed in patients [27]. Further- more, recent studies in human neural progenitors lack- Review ing one copy of CHD8 support this notion, as it revealed Convergent evidence for Wnt signaling many target genes controlled by CHD8 that are involved One pathway highlighted in the multitude of genetic in the regulation of spine head size [34, 39, 40]. However studies is the Wingless (Wnt) signaling. This pathway is a recent study discovered that CHD8 is in fact a positive highly studied and conserved from lower to higher or- regulator of Wnt/β-catenin signaling NPCs, while simul- ganisms, where it plays a variety of roles in almost all taneously demonstrating that it negatively regulates the tissues. Broadly speaking, Wnt signaling in the brain can pathway in non-neuronal cell lines [41]. Given
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